Oral antiretroviral (ARV) pre-exposure prophylaxis (PrEP) holds enormous potential for expanding prevention strategies for adolescents, who account for 39% of all new global infections. We urgently need to engage in exploratory research of PrEP as an adolescent prevention strategy given growing evidence on safety and partial efficacy of adult PrEP accompanied by the recent launch of initial adolescent safety trials We propose an exploratory R21 study to investigate adolescents' and clinicians' understandings of PrEP in South Africa, the country with the largest number of people living with HIV. This research can advance HIV prevention science by improving our understanding of the behavioral and social processes that may potentiate future implementation of adolescent PrEP trials, and to optimize the translation of clinical findings into public health practice through effective messaging about PrEP safety and efficacy. Adolescents undergo unique developmental milestones which are likely to influence PrEP acceptability, willingness to use or to support others' use of PrEP, understandings of messages about PrEP effectiveness, and behavioral decisions in different ways than adults. We focus on endemic settings to leverage lessons from adolescents navigating serodiscordant relationships and to capture PrEP relevant experiences of perinatally infected children who confront challenges relating to ARV adherence, balancing risk for infection of serodiscordant partners with decisions to initiate sex, and fertility desires We compare HIV-positive and HIV-negative adolescents' understandings of PrEP since acceptability, willingness to use or to support partner's use, and predicted behavioral impacts of PrEP may vary by HIV status. We explore how adolescents interpret messages of PrEP partial efficacy as derived from adult trials, and how expectations of PrEP efficacy might affect uptake, adherence, and risk compensation. We triangulate adolescent and clinician perspectives, and explore clinician's views on potential barriers and facilitators in PrEP implementation in resource-constrained endemic settings. Our immediate goals are to understand adolescent-specific factors that affect the design of safety, feasibility, and efficacy of PrEP trials for adolescents (d18 years) and to develop an initial empirical conceptual model to guide adolescent-tailored PrEP messaging to prevent behavioral disinhibition. We propose three aims: 1) to use focus groups (k = 6-10) with HIV-positive and HIV-negative adolescents to explore knowledge, acceptability, willingness to use PrEP or to support partner use, and how about PrEP education based on adult efficacy trials may influence uptake, adherence, and risk compensation; 2) to use in-depth interviews (n = 24- 32) with adolescents to explore Aim 1 topics in more depth and to probe for sensitive issues such as how stigma and disclosure might affect acceptability of PrEP; and 3) to use individual interviews (n = 20-30) with clinicians to understand opinions of PrEP, willingness to prescribe, barriers and facilitators for implementing PrEP, and how to support adherence and protective behaviors during future rollout of adolescent PrEP.